Abstract
BackgroundIn chronic hepatitis C virus (HCV) infection, liver tissue pathology and HCV genotype are important determinants of clinical and/or treatment-related outcome. Although consistent epidemiological and/or molecular-biological clues derived from different studies on single virus-host interactions are meanwhile published, the in vivo transcriptional responses and cellular pathways affected in >1 key aspects of the disease or treatment process are far from being understood.MethodsMicroarray analysis was performed in peripheral whole blood (PB) samples from 36 therapy-naïve HCV-infected patients with known liver histology. Linear regression analysis identified gene expression profiles significantly correlating (P < 0.015) with ≥1 out of 7 variables: sustained viral response (SVR), viral non-response (NR), end of treatment viral response (ETR), viral breakthrough (VB), HCV genotype (Gt. 1 vs. Gt. 2/3), stage of hepatic fibrosis [St. 0/1 vs. St. 2/3/4] and grade of hepatic inflammation (Gr. 0/1 vs. Gr. 2/3/4). Correlation values across all seven contrasts were considered for hierarchical clustering (HCL).ResultsA total of 1,697 genes showed ≥1 significant correlation results and genes involved in cell differentiation (183), immune response (53), and apoptosis (170) were leading fractions. HCL grouped the genes into six major clusters. Functional annotation analysis using DAVID (http://david.abcc.ncifcrf.gov) revealed that expression profiles that best linked these variables were highly enriched in cytokine/chemokine activity (Fisher-exact P < 0.0001) and specific biological module-centric algorithms finally led our focus on four out of fifty-three immune response genes: SMAD family member 3 (SMAD3), interleukin 1 receptor accessory protein (IL1RAP), tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), and chemokine ‘C-C motif’ receptor 5 (CCR5). Of those, TNFRSF1A and CCR5 showed significant correlation with two out of seven variables based on microarray and/or quantitative real-time polymerase chain reaction (qRT-PCR) data.ConclusionWe identified molecular targets of the innate and adaptive immune system and validated their transcriptional specificity in vivo suggesting significant involvement in two unique outcomes during HCV treatment.
Highlights
In chronic hepatitis C virus (HCV) infection, liver tissue pathology and HCV genotype are important determinants of clinical and/or treatment-related outcome
Histological grade of hepatic inflammation and stage of hepatic fibrosis as well as HCV genotype (Gt.) are considered significant determinants of clinical outcome in terms of progression of liver disease, and/or response to treatment in patients with chronic HCV infection as: (1) persistent he-patic inflammation is considered a major determinant of liver fibrosis progression towards cirrhosis [2]; (2) previous research has detected an association between advanced hepatic fibrosis and lower rates of successful response (sustained viral response (SVR)) to Interferon-alpha [3] or pegylated Interferon-alpha and Ribavirin (Peg-IFN-α/RBV) [4]; and (3) patients infected with Gt.2 or Gt.3 (80%) regularly achieve higher SVR rates relative to those infected with Gt.1 or Gt.4 (50%) [5]
Gene expression profiles (n = 1,697) that reached at least one highly significant correlation result (r > 0.4 or r < −0.4, P < 0.015) were selected and further subjected to unsupervised hierarchical clustering (HCL) using linear regression values calculated across all seven contrasts (Figure 1)
Summary
In chronic hepatitis C virus (HCV) infection, liver tissue pathology and HCV genotype are important determinants of clinical and/or treatment-related outcome. We analyzed gene expression profiles in peripheral whole blood (PB) of therapy-naïve HCV-infected subjects that underwent liver biopsy in order to identify gene expression patterns reflective of host biology that is linked to ≥1 clinical and/or viral stratification clusters To this end, rigorous multicontrast linear regression analysis was performed on gene expression profiles against seven variables reflecting the state of cHCV with or without therapy. Our final results demonstrated that tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and chemokine ‘C-C motif’ receptor 5 (CCR5) correlated significantly with two out of seven variables These findings, which have been successfully validated by quantitative real-time polymerase chain reaction (qRT-PCR) in a fraction of patients, represent a promising basis for future molecular research aimed to provide comprehensive insights into genes/pathways with multiple in vivo impacts in viral hepatitis and/or develop anti-HCV therapies that target these genes/pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
